Tumor progression and resistance to therapy are strongly influenced by the tumor microenvironment (TME), a complex network of stromal cells, immune cells, extracellular matrix, and signaling molecules. While traditional cancer research has emphasized tumor-intrinsic factors such as genetic mutations and oncogenic signaling, growing evidence identifies the TME as a key driver of therapeutic failure. The TME promotes resistance through multiple mechanisms, including impaired drug delivery, immune suppression, metabolic reprogramming, and activation of survival pathways. Conditions such as hypoxia and acidosis, along with interactions between tumor and stromal cells, further reinforce resistant phenotypes.

Recent advances highlight the potential of targeting the TME to overcome these barriers. Strategies such as modulating immune cell activity, targeting cancer-associated fibroblasts, and disrupting tumor–stroma communication have shown promise in enhancing treatment efficacy. Integrating TME-focused interventions with conventional therapies may improve tumor sensitivity and patient outcomes. Understanding the dynamic role of the TME provides a foundation for developing more effective, multidimensional cancer treatment strategies.